Field of the Invention
The present invention relates generally to the field of cancer treatment, and more particularly, to a soluble CD80 protein that interacts with programmed death ligand 1 (PD-L1) and thereby inhibiting the interaction of PD-L1 with T-cell expressed programmed death 1 (PD1) receptor, and thus, minimizing PD-L1 mediated immune suppression.
Description of the Related Art Technical Field
Tumor-induced immune suppression is a major obstacle for therapies aimed at activating an individual's immune system to eliminate autologous cancer cells. Various mechanisms contribute to this immune suppression. A major contributor is the co-inhibitory molecule Programmed Death Ligand-1 (PDL1), also known as B7 homolog 1 (B7-H1) or CD274. PDL1 obstructs anti-tumor immunity by (i) tolerizing tumor-reactive T cells by binding to its receptor PD1 (CD279) on T cells (1, 2); (ii) rendering tumor cells resistant to CD8+ T cell and FasL-mediated lysis by PD-1 signaling through tumor cell-expressed PDL1 (3); (iii) tolerizing T cells by reverse signaling through T cell-expressed CD80 (4, 5); and (iv) promoting the development and maintenance of induced T regulatory cells (6).
Most malignant cells constitutively express or are induced by IFNγ to express PDL1 (1, 3, 7, 8), and the loss of tumor suppressor genes can increase tumor cell expression of PDL1 (9). Expression of PDL1 by human cancer cells is a marker for poor prognosis (7, 10, 11). Therefore, PDL1 is a major obstacle to natural anti-tumor immunity and to cancer immunotherapies requiring activation of host T cell-mediated anti-tumor immunity. This concept is supported by studies demonstrating that antibody blocking of PDL1-PD1 interactions improves T cell activation and reduces tumor progression, and that antibody blocking of PDL1 reverse signaling through T cell-expressed CD80 prevents T cell energy (5). The critical role of PDL1 has recently been further supported by phase I/II clinical trials in which mAb to PDL1 or PD1 have delayed tumor progression in some patients with cutaneous melanoma, renal cell carcinoma, non-small cell lung cancer, and hormone refractory prostate cancer (16-20). Although antibodies to PDL1 or PD1 have shown therapeutic efficacy in a subset of cancer patients, the majority of patients do not benefit from antibody treatment.
Thus, there is needed a novel mechanism for regulating PD-L1 function that will lead to a new universally applicable treatment for minimizing PD-L1-mediated immune suppression in cancer patients and that is more effective than currently available mAbs to PD-1 or PD-L1.